Identification of a high affinity FcgammaRIIA-binding peptide that distinguishes FcgammaRIIA from FcgammaRIIB and exploits FcgammaRIIA-mediated phagocytosis and degradation.
FcgammaRIIA is a key activating receptor linking immune complex formation with cellular effector functions. FcgammaRIIA has 93% identity with an inhibitory receptor, FcgammaRIIB, which negatively regulates FcgammaRIIA. FcgammaRIIA is important in the therapeutic action of several monoclonal antibodies. Binding molecules that discriminate FcgammaRIIA from FcgammaRIIB may optimize receptor activity and serve as a lead for development of therapeutics with FcgammaRIIA as a key target. Here we report the use of phage display libraries to select short peptides with distinct FcgammaRIIA binding properties. An 11-mer peptide (WAWVWLTETAV) was characterized that bound FcgammaRIIA with a K(d) of 500 nm. It mediated cell internalization and degradation of a model antigen. The peptide-binding site on FcgammaRIIA was shown to involve Phe(163) and the IgG binding amino acids Trp(90) and Trp(113). It is thus overlapping but not identical to that of IgG. Neither activating receptors FcgammaRI and FcgammaRIII, nor FcgammaRIIB, all of which lack Phe(163), bound the peptide.
Berntzen
Gøril
G
Department of Molecular Biosciences, University of Oslo, Oslo, Norway.
Andersen
Jan Terje
JT
Ustgård
Kristine
K
Michaelsen
Terje E
TE
Mousavi
Seyed Ali
SA
Qian
Julie Dee
JD
Kristiansen
Per Eugen
PE
Lauvrak
Vigdis
V
Sandlie
Inger
I
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D010587:Phagocytosis; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020349:Surface Plasmon Resonance
C080568:Fc gamma receptor IIA; C080571:Fc gamma receptor IIB; D010455:Peptides; D017452:Receptors, IgG; D011994:Recombinant Proteins